CapG调控PI3K信号通路影响乳腺癌内分泌治疗的疗效及机制研究

Although endocrine therapy targeting estrogen receptor (ER) signaling prevent disease recurrence in the majority of patients with hormone-dependent breast cancer, part of patients exhibit de novo or acquired resistance. Our previous studies have shown that CapG, whose expression was closely correlated with ER, could bind to the promoter of PI3KR to activate its transcription. In breast cancer cell line, CapG could decrease the sensitivity to tamoxifen, while PI3K inhibitor blocked this effect. We speculated that CapG was involved in the endocrine resistance through regulation of PI3K signaling pathway. Here we aim at examining the precise mechanism through which CapG activated the PI3K signaling pathway and the function of CapG in the crosstalk of ER and PI3K by Dual-Luciferase assay and ChIP assay. Then whether endocrine therapy efficacy will be improved by interfering CapG will be evaluated in breast cancer cell lines and nude mice models. The association between CapG expression and metastatic breast cancer patients during endocrine therapy will also be examined. Taken together, these studies may lead to a new endocrine treatment strategy by targeting CapG in breast cancer. Meanwhile, through this project we want to demonstrate that CapG could be used as a biomarker for predicting efficiency or resistance to endocrine therapy, and as novel therapeutic target for personalized treatment in ER positive patients.

内分泌治疗耐药是目前雌激素受体阳性乳腺癌治疗的一大难题，研究表明PI3K信号通路是克服内分泌耐药的关键靶点。我们前期工作发现CapG可以通过结合PI3KR启动子促进其转录，激活PI3K信号通路；同时CapG可以明显降低雌激素受体阳性乳腺癌细胞株对他莫昔芬的敏感性，而PI3K抑制剂则可阻断这一效应，提示CapG可能通过调控PI3K信号通路参与内分泌耐药。本课题拟系统研究CapG调控PI3K信号通路的具体机制；通过质谱分析寻找调控PI3K的CapG转录复合物；在细胞及动物水平，通过干预CapG表达，研究CapG对内分泌药物治疗疗效的影响；同时结合临床分析内分泌治疗疗效与CapG表达的相关性。本研究旨在阐明CapG调控PI3K的具体机制，明确CapG是否可以作为预判患者内分泌治疗疗效的指标，为临床乳腺癌内分泌治疗耐药提供新的分子标记物及干预靶点，为患者的个体化治疗提供依据。

雌激素受体α（ERα）阳性乳腺癌的内分泌耐药是乳腺癌治疗耐药的主要问题，也是乳腺癌患者死亡的主要原因之一。各种分子信号传导，包括PI3K信号通路的活化，已被证明与内分泌耐药相关，但其潜在机制尚未完全了解。我们研究发现肌动蛋白结合蛋白CapG的表达与ER+乳腺癌细胞的三苯氧胺耐药显著相关。高CapG水平与乳腺癌患者无复发生存（RFS）以及PI3K/Akt信号的高度激活有关。从机制上讲，CapG促进PI3Kr1/p50转录，导致PI3K/AKT激活增加。有趣的是，我们发现CapG与PI3KR1/p50异构体特异启动子结合，在该启动子位置，它与P300/CBP相互作用，招募CBP/P300到启动子区域，从而通过促进组蛋白H3K27乙酰化来增加PI3KR1/P50的转录。相似的，用P300/CBP特异性抑制剂C646抑制P300/CBP可以显著降低CapG依赖的PI3KR1/P50的转录上调，并抑制PI3K/AKT信号通路活化，从而提高ER+乳腺癌细胞对三苯氧胺治疗的敏感性。我们的研究数据表明，CapG可以作为ERα+乳腺癌患者三苯氧胺疗效的新的预测标记物以及一个潜在的治疗靶点，高表达CAPG的乳腺癌患者在联合三苯氧胺及PI3K信号通路抑制剂治疗中获益。